The Dana Farber/Harvard Cancer Center (DF/HCC) multiple myeloma (MM) SPORE renewal application consists of 6 Research Projects and 3 Cores, as well as the Career Development and Developmental Research Programs. During the previous funding period, we have capitalized on the complementary strengths of the research, clinical expertise, and facilities of the Harvard affiliated institutions including Dana- Farber Cancer Institute, Harvard Medical School, Harvard School of Public Health, as well as the Mayo Clinic. We have successfully translated multiple novel agents from the bench to the bedside and FDA approval for treatment of MM. Three projects in this renewal SPORE application have evolved from prior Developmental Projects, and two Career Development awardees are now Principal Investigator or Co- Investigators of new projects. One of the new projects focuses on genotypic and epidemiologic studies in multi-ethnic population, reflecting our emphasis on minority studies. We have established a collaborative effort, both in preclinical cellular and molecular studies and in joint clinical protocols. The group as a whole has a long-term commitment to translational MM research, with the necessary administrative, basic science, and clinical infrastructure. At these well established centers, more than 750 new patients with MM are evaluated annually, as well as 10,000 outpatient visits for established patients with plasma cell dyscrasias. The spectrum of diseases evaluated spans from monoclonal gammopathy of unclear significance to plasma cell leukemia. Each center has appropriate scientific and institutional review boards, as well as protocol audit and quality control centers, to conduct cutting edge translational research. There are presently more than 50 active protocols evaluating therapies including novel drugs, immune treatments, improved stem cell transplantation, and supportive therapies in MM. This large combined patient base assures rapid accrual and evaluation of the therapeutic efficacy of novel agents identified in this program. Success of both the preclinical and clinical components of this Program will be dependent upon synergy and communication between these centers. To assure this end, we have set up an Internet site that allows access to all the Principal Investigators to the preclinical data generated in joint research efforts. Similarly, data from the joint clinical protocol trials will also be deposited in this secure web site to allow a seamless and uniform conduct of clinical studies at these sites. Currently there is systematic quality-controlled exchange of bone marrow and blood samples for correlative basic laboratory studies. The overall theme of the DF/HCC myeloma SPORE is to identify and evaluate novel targeted therapies. The translational nature of the SPORE is highlighted by the fact that most of our projects have emanated from clinical studies from the outset. Specific Projects are (1) Overcoming Proteasome-lnhibitor Resistance in Multiple Myeloma; (2) Targeting Telomere Expansion Mechanisms For Myeloma Therapy; (3) Targeting the Wnt Pathway for Treatment of Multiple Myeloma; (4) Targeting Activation of NF-?B Pathways in Multiple Myeloma; (5) Molecular Markers of Plasma Cell Neoplasm Evolution; and (6) Identifying High Risk Genotypes for Multiple Myeloma: A Collaborative Multi-Ethnic Case-Controlled Study. Core resources include Administrative Communication and Planning Core (1), Tissue Core (2), and Biostatistics and Bioinformatics Core (3). This Program therefore represents the integrated efforts of institutions with a unique and long track record of basic and clinical research expertise in MM, now joining together to more rapidly move rational novel targeted therapies from the laboratory to clinical protocols to improve patient outcome in MM.